Intravenous Immunoglobulin Suppresses Chemotherapy-Induced Peripheral Neurotoxicity Via Macrophage Modulation in Rats and Mice

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Jun Tanaka Masahiko Kajii


Chemotherapy-induced peripheral neurotoxicity (CIPN) is a serious adverse effect that leads to treatment discontinuation by patients receiving anticancer therapy. Treatment discontinuation is a serious and life-threatening problem for patients with cancer; hence, there is a need for drugs that suppress the induction of CIPN by anticancer drugs. Here, using rat and mouse models, we showed that intravenous immunoglobulin (IVIg) can suppress CIPN induced by not only paclitaxel but also by doxorubicin. Furthermore, the suppressive effect of IVIg is eliminated when macrophages are depleted. Here, we proposed two novel independent mechanisms underlying the alleviation of CIPN by IVIg. First, IVIg suppresses CIPN in a macrophage-dependent manner. Second, IVIg combined with anticancer drugs can avoid restrictions on the use of anticancer drugs owing to CIPN induction. However, further research is necessary for the bench-to-bedside translation of these novel applications of IVIg. Our findings lay a strong foundation for research on IVIg therapeutics.

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TANAKA, Jun; KAJII, Masahiko. Intravenous Immunoglobulin Suppresses Chemotherapy-Induced Peripheral Neurotoxicity Via Macrophage Modulation in Rats and Mice. Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 06 dec. 2022. doi:
Research Articles


1 Brown, M. R., Ramirez, J. D. & Farquhar-Smith, P. Pain in cancer survivors. British journal of pain. 2014; 8(4): 139-53. doi:10.1177/2049463714542605.
2 Flatters, S. J. L., Dougherty, P. M. & Colvin, L. A. Clinical and preclinical perspectives on Chemotherapy-Induced Peripheral Neuropathy (CIPN): a narrative review. British journal of anaesthesia. 2017; 119(4): 737-749. doi:10.1093/bja/aex229.
3 Shimozuma, K. et al. Taxane-induced peripheral neuropathy and health-related quality of life in postoperative breast cancer patients undergoing adjuvant chemotherapy: N-SAS BC 02, a randomized clinical trial. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2012; 20(12): 3355-64. doi:10.1007/s00520-012-1492-x.
4 Hershman, D. L. et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014; 32(18): 1941-67. doi:10.1200/jco.2013.54.0914.
5 Bruton, O. C. Agammaglobulinemia. Pediatrics. 1952; 9(6): 722-8.
6 Ballow, M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. The Journal of allergy and clinical immunology. 2011; 127(2): 315-23; quiz 324-5. doi:10.1016/j.jaci.2010.10.030.
7 Anthony, R. M., Wermeling, F. & Ravetch, J. V. Novel roles for the IgG Fc glycan. Annals of the New York Academy of Sciences. 2012; 1253: 170-80. doi:10.1111/j.1749-6632.2011.06305.x.
8 Yamada, H. et al. Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial. EClinicalMedicine. 2022; 50: 101527. doi:10.1016/j.eclinm.2022.101527.
9 Ibanez, C. & Montoro-Ronsano, J. B. Intravenous immunoglobulin preparations and autoimmune disorders: mechanisms of action. Current pharmaceutical biotechnology. 2003; 4(4): 239-47.
10 Tanaka, J. et al. Intravenous immunoglobulin suppresses IL-10 production by activated B cells in vitro. Open Journal of Immunology. 2012; Vol.02No.04: 12. doi:10.4236/oji.2012.24019.
11 De Groot, A. S. et al. Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood. 2008; 112(8): 3303-11. doi:10.1182/blood-2008-02-138073.
12 Meregalli, C. et al. High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats. Journal of neuroinflammation. 2018; 15(1): 232. doi:10.1186/s12974-018-1270-x.
13 Meregalli, C. et al. Human Intravenous Immunoglobulin Alleviates Neuropathic Symptoms in a Rat Model of Paclitaxel-Induced Peripheral Neurotoxicity. International journal of molecular sciences. 2021; 22(3. doi:10.3390/ijms22031058.
14 Nakae, T., Hirayama, F. & Hashimoto, M. [Neutralizing activity of human immunoglobulin preparation against toxic shock syndrome toxin-1]. Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases. 2002; 76(3): 195-202.
15 Nakae, T., Tanaka, J., Nakano, A. & Ono, Y. Complement-mediated bactericidal effect of antibodies in human intravenous preparation against multi-drug resistant pseudomonas aeruginosa. The Japanese journal of antibiotics. 2008; 61(6): 379-87.
16 Tanaka, J. et al. Effective concentration of intravenous immunoglobulin for neutralizing Panton-Valentine leukocidin in human blood. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2018. doi:10.1016/j.jiac.2017.12.023.
17 Tanaka, J. et al. Complement-mediated bacteriolysis after binding of specific antibodies to drug-resistant Pseudomonas aeruginosa: morphological changes observed by using a field emission scanning electron microscope. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2010; 16(6): 383-7. doi:10.1007/s10156-010-0074-4.
18 Tanaka, J. et al. Intravenous Immunoglobulin Suppresses Abortion Relates to an Increase in the CD44bright NK Subset in Recurrent Pregnancy Loss Model Mice. Biology of reproduction. 2016; 95(2): 37. doi:10.1095/biolreprod.116.138438.
19 Kajii, M. et al. Intravenous immunoglobulin preparation attenuates neurological signs in rat experimental autoimmune neuritis with the suppression of macrophage inflammatory protein -1alpha expression. Journal of neuroimmunology. 2014; 266(1-2): 43-8. doi:10.1016/j.jneuroim.2013.10.011.
20 Kajii, M. et al. Prevention of excessive collagen accumulation by human intravenous immunoglobulin treatment in a murine model of bleomycin-induced scleroderma. Clinical and experimental immunology. 2011; 163(2): 235-41. doi:10.1111/j.1365-2249.2010.04295.x.
21 Flatters, S. J. & Bennett, G. J. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain. 2004; 109(1-2): 150-61. doi:10.1016/j.pain.2004.01.029.
22 Nieto, F. R. et al. Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice. Pain. 2008; 137(3): 520-31. doi:10.1016/j.pain.2007.10.012.
23 Cassetta, L. & Pollard, J. W. Targeting macrophages: therapeutic approaches in cancer. Nature reviews. Drug discovery. 2018; 17(12): 887-904. doi:10.1038/nrd.2018.169.